The important milestones of clinical trial evolution

Mak Wen Yao , 20 Jun 2017

Randomisation is important in clinical trials to protect against any potential bias – most notably selection bias – and also safeguards against any accidental biases.

Clinical trials have been long considered as an integral part of medical sciences. It is only through rigorous experimentation and observation that we can conclude with confidence that a particular medication works as intended. In fact, participation in clinical trials has become a routine for healthcare professionals in many developed countries, and such practice is beginning to gain a foothold in Malaysia.

A well-designed clinical trial is inherently complex and will typically contain essential features such as the use of placebo, subject randomisation and double-blind procedure. Nonetheless, not all of us are aware of the origins of these concepts and may not appreciate their functions and added sophistication to the already detailed trial design.

Let’s take a stroll down the history lane of clinical trials – and rediscover its development through the ages.

The first clinical trial

The first recorded attempt to compare the efficacy of a novel therapy with the established "gold standard" treatment was conducted by the famous barber-surgeon, Ambroise Paré, in 1537 on the battlefield. The “experiment” was rather an accidental discovery for Paré as he ran out of the boiling oils used to cauterise wounds of injured soldiers.

Instead, Paré opted to use a soothing balm, or a “digestive” as Paré called it – consisting egg yolks, rose oil and turpentine. To his surprise, the alternative treatment had worked wonders for the soldiers. He described the soldiers who received the alternative “feeling but little pain, their wounds neither swollen nor inflamed, and having slept through the night”.

The first controlled clinical trial

Many researchers with a pair of keen eyes would immediately point out the Paré experiment was flawed: the soldiers treated with the "digestives of egg yolks, rose oil and turpentine" may have less severe wounds than those treated with boiling oil. They may rightfully say so. The concept of a controlled clinical trial did not exist until almost 200 years later, when James Lind conducted the famous trial on scurvy.

At that time, scurvy was a common illness among seafarers and a particularly problematic disease to the British navy. In 1747, Dr James Lind was on board the British naval ship Salisbury where many of the crew members were debilitated by the disease.

Instead of succumbing to misery, Lind devised a parallel-arm medical experiment to cure scurvy. He divided 12 sailors into six groups of two. Each group would receive a different treatment: cider, a few drops of weak acid, vinegar, seawater, nutmeg and barley water, or oranges and lemons.

At the end of the study, the two patients who were put on oranges and lemons had fully recovered from the sickness. Lind wrote, in his 1753 “Treatise on Scurvy”, that “the most sudden and visible good effects were perceived from the use of oranges and lemons", signifying the efficacy of the management choice.

The arrival of placebo

The next breakthrough in clinical trial design did not emerge until more than 100 years later when physician Austin Flint conducted an experiment to compare the effect of an active treatment to a dummy remedy.

Flint used a herbal extract in place of the active treatment, of which he called the "placeboic remedy" where "the favourable progress of the cases was such as to secure for the remedy generally the entire confidence of the patients".

An interesting note to Flint "placebo" as compared to today's standard is that modern placebo must appear identical to the active treatment, and must not contain any ingredients that may possibly exert any effect, no matter how insignificant.

The first double-blind controlled trial

To further ascertain the trial results are not tainted by any form of bias, either from the patients or investigators themselves, a double-blind study will be necessary. The Medical Research Council (MRC) UK was purportedly the first to conduct a double-blind trial with concurrent controls in the general populations.

The trial was conducted between the years of 1943 – 1944, to investigate the effect of patulin treatment on the common cold. Interestingly, as written by Phillip D'Archy Hart in 1999, the trial was probably the last that utilised a non-randomised study design.

The nationwide study started in Cardiff, where both doctors and patients were blinded to the type of treatment administered. Unfortunately, the trial demonstrated no positive effect of patulin on common cold, “… a disappointing outcome for a rigorously controlled trial and perhaps the last of its kind,” as Hart wrote.

The first randomised curative trial

The clinical trial to investigate the effect of Streptomycin on tuberculosis, conducted by the MRC in 1947-1948, was widely regarded as the first randomised curative trial. Randomisation is important in clinical trials to protect against any potential bias, most notably selection bias, and also safeguards against any accidental biases.

Dr Phillip D’Archy Hart wrote in his 1999 article in the BMJ about the significance of the Streptomycin-Tuberculosis trial.

“The trial heralded the general conversion of clinical scientist to randomisation” and had set the stage for a more robust trial design for many decades to come.” MIMS

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